Physiogenomic resources for rat models of heart, lung and blood disorders

Malek, Renae L.; Wang, Hong Ying; Kwitek, Anne E.; Greene, Andrew S.; Bhagabati, Nirmal; Borchardt, Gretta; Cahill, Lisa Sowle; Currier, Tracey; Frank, Bryan; Fu, Xianping; Hasinoff, Michael J.; Howe, Eleanor; Letwin, Noah E.; Luu, Truong; Saeed, Alexander I.; Sajadi, Hedieh; Salzberg, Steven L.; Sultana, Răzvan; Thiagarajan, Mathangi; Tsai, Jennifer; Veratti, Kathleen; White, Joseph A.; Quackenbush, John; Jacob, Howard J.; Lee, Norman H.

doi:10.1038/ng1693

Cited by 44 publications

(44 citation statements)

References 27 publications

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“…The present studies highlighted that CSS panels, although capable of revealing some complex disease associations (15,30), lacked the breadth to identify distant interacting genetic factors characteristic of a complex disease like ARD. RNA-Seq allows for more complete documentation of genetic changes relevant to complex disease etiology (31).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory priming predisposes mice to age-related retinal degeneration

Mustafi¹,

Maeda²,

Kohno³

et al. 2012

J. Clin. Invest.

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Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Postmitotic neurons, such as photoreceptor cells in the retina and epithelial cells in the adjacent retinal pigmented epithelium, are especially susceptible to cellular senescence, which contributes to age-related retinal degeneration (ARD). The multigenic and complex etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the genetic differences that drive ARD pathogenesis, we studied A/J mice, which develop ARD more pronounced than that in other inbred mouse models. Although our investigation of consomic strains failed to identify a chromosome associated with the observed retinal deterioration, pathway analysis of RNA-Seq data from young mice prior to retinal pathological changes revealed that increased vulnerability to ARD in A/J mice was due to initially high levels of inflammatory factors and low levels of homeostatic neuroprotective factors. The genetic signatures of an uncompensated preinflammatory state and ARD progression identified here aid in understanding the susceptible genetic loci that underlie pathogenic mechanisms of age-associated disorders, including several human blinding diseases. IntroductionAge-related disorders arise from failure of tissue maintenance and repair pathways that are accelerated by certain inherited and acquired factors (1). Long-lived nondividing cells, such as neurons, have markedly reduced tolerance to damage (2), and thus exhibit the most pronounced age-related changes. Neuronal cells in the retina are an especially attractive model system to study this phenomenon, owing to their accessibility and wellunderstood physiology. Rod and cone photoreceptors are retinal neuronal cells that initiate visual perception, a function requiring a competent neighboring retinal pigmented epithelium (RPE) for their normal operation (3). In postmitotic cells such as these photoreceptor and RPE cells, cellular senescence can ensue when shed oxidized photoreceptor outer segments (POS) are inadequately phagocytosed and digested by the RPE. This results in accumulation of damaged proteins, formation of toxic metabolic byproducts, inflammatory cell invasion, and cell death. RPE cells are the most affected because, in addition to processing POS, they serve as the conduit between photoreceptors and the choroidal blood supply for metabolite exchange (4). Acquisition of senescence-associated pathology stimulates cells to secrete various factors that contribute to tissue dysfunction. Conversely, adequate clearance of such cells can delay the onset of age-related tissue pathology (5).Aging laboratory experimental animals are important models for studying age-related pathology, especially neurodegenerative disorders, which have been shown to be affected by their genetic backgrounds (6, 7). The A/J inbred mouse ...

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Section: Discussionmentioning

confidence: 99%

Inflammatory priming predisposes mice to age-related retinal degeneration

Mustafi¹,

Maeda²,

Kohno³

et al. 2012

J. Clin. Invest.

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“…We also compared our microarray data against available in vivo lung tissue-based PH microarray studies reported in PubMed, representing work across a variety of species (human, mouse, rat) (10,11,18,29). For example, one previous study utilized for comparison included significantly differentially expressed genes between normoxia and hypoxia conditions for male Dahl SS rats (29). A list of significantly differentially expressed genes in Homo sapiens diagnosed with PH was taken from Table 3 and Supplemental Table S1 from a study by Geraci et al (10).…”

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confidence: 99%

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Moreno‐Vinasco

Gomberg‐Maitland

Maitland

et al. 2008

Physiological Genomics

100

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Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 33: 278 -291, 2008. First published February 26, 2008 doi:10.1152/physiolgenomics.00169.2007.-Pulmonary hypertension (PH) and cancer pathology share growth factor-and MAPK stressmediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1-3, PDGF receptor (PDGFR)-␤, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxiaexposed control animals, four groups were maintained at 10% inspired O 2 fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/ sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]-and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change Ͼ1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target. microarrays; SU-5416; bioinformatics PULMONARY ARTERIAL HYPERTENSION (PH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) with a mean pressure of Ͼ25 mmHg at rest or 30 mmHg during exercise (43), with severe PH exhibiting PAP values Ͼ50 mmHg (2, 59). Severe PH manifests as both an acute and a chronic presentation, with chronic PH leading to progressive right ventricular (RV) systolic pressure overload and ventricular dilatation, resulting in gradual RV dysfunction, heart failure, and death (21). Idiopathic PH has an estimated annual incidence of 1-2 per million (1) with mutations of the bone morphogenetic protein receptor type 2 gene (BMPR2) identified in ϳ50% of cases of familial PH (7). However, because only 20% of persons with a BMPR2 mutation develop PH (32), external stimuli, coupled with a susceptible genetic profile,...

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“…86-90 Physiogenomics has also been successfully applied in rodent animal models by others. 63 Here we demonstrated that physiogenomics also applies to sensorial stimuli, specifically acoustic patterns, as exemplified by the oddball task. Consistent with a targeted, hypothesis-driven query, we compared genes involved in dopaminergic and serotonergic neurotransmitter systems and determined a high level of association to DBH and DRD4, which is supported by prior pathophysiological and genetic associations to schizophrenia and uncovered a new association to HTR3A.…”

Section: Discussionmentioning

confidence: 80%

Physiogenomic Analysis of Localized fMRI Brain Activity in Schizophrenia

et al. 2008

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The search for genetic factors associated with disease is complicated by the complexity of the biological pathways linking genotype and phenotype. This analytical complexity is particularly concerning in diseases historically lacking reliable diagnostic biological markers, such as schizophrenia and other mental disorders. We investigate the use of functional magnetic resonance imaging (fMRI) as an intermediate phenotype (endophenotype) to identify physiogenomic associations to schizophrenia. We screened 99 subjects, 30 subjects diagnosed with schizophrenia, 13 unaffected relatives of schizophrenia patients, and 56 unrelated controls, for gene polymorphisms associated with fMRI activation patterns at two locations in temporal and frontal lobes previously implied in schizophrenia. A total of 22 single nucleotide polymorphisms (SNPs) in 15 genes from the dopamine and serotonin neurotransmission pathways were genotyped in all subjects. We identified three SNPs in genes that are significantly associated with fMRI activity. SNPs of the dopamine beta-hydroxylase (DBH) gene and of the dopamine receptor D4 (DRD4) were associated with activity in the temporal and frontal lobes, respectively. One SNP of serotonin-3A receptor (HTR3A) was associated with temporal lobe activity. The results of this study support the physiogenomic analysis of neuroimaging data to discover associations between genotype and disease-related phenotypes.

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Physiogenomic resources for rat models of heart, lung and blood disorders

Cited by 44 publications

References 27 publications

Inflammatory priming predisposes mice to age-related retinal degeneration

Inflammatory priming predisposes mice to age-related retinal degeneration

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Physiogenomic Analysis of Localized fMRI Brain Activity in Schizophrenia

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